This well known variant is associated with myeloproliferative diseases: it is used as a diagnostic, providing supporting evidence in individuals who already have symptoms. It is seen as an acquired (not inherited) mutation, one of an accumulation of changes that leads to the development of these cancer-like diseases. It is possible to see this variant in whole genome data or genotyping from blood-derived DNA — but it is unclear how to view the presence of the variant in individuals who don’t have symptoms of the disease. Data from Nielsen et al. suggests that such carriers are at much higher risk of developing myeloproliferative disease or other blood cancer (with roughly 50% of still-living individuals developing these diseases by around 10 years after initial samples — but these numbers are extremely uncertain).

active in absence of erythropoietin signalling, loss-of-heterozygosity observed clinically is consistent with suppression of this activity gain by wildtype JAK2, cell lines with JAK2-V617F became able to grow independently of growth factors, mice with JAK2-V617F bone marrow transplants had significantly high volume of red blood cells in their blood.

See James C et al. 2005 (15793561).

Case/Control

5

p=7*10^-22 for myeloproliferative disease and p=2*10^-32 for hematological cancer

See Nielsen C et al. 2011 (21160067).

Familial

No familial data; cases to date appear to be acquired mutations (rather than inherited)

Clinical importance

Severity

4

Polycythemia vera, Essential thrombocytosis, Myelofibrosis

Treatability

4

Polycythemia vera and essential thrombocytosis are fairly treatable

Penetrance

4

Chance for subsequent development of myeloproliferative disorder and/or blood cancer unclear, may be 20%-50% range.

See Nielsen C et al. 2011 (21160067).

Impact

High clinical importance, pathogenic

(The "high clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

dominant

Summary of published research, and additional commentary

This variant was discovered in the context of myeloproliferative diseases, and is a standard component in the diagnosis of these diseases — patients which have symptoms of the disease are tested for the presence of this variant, which is viewed as confirmatory evidence. How to react when an assumed-healthy individual presents with the variant is largely unknown. The variant has to date been reported as an acquired (not inherited) pre-cancerous mutation in blood stem cells. As genotyping / exome sequencing / whole genome sequencing are often performed using blood-derived DNA, this is sampling the appropriate tissue for detecting the acquired mutation.

The most relavent study is probably Nielsen et al. (data from the Copenhagen City Heart Study), which found 18 individuals with the variant. They report using the testing method of Baxter et al., implying a low sensitivity examination of Sanger sequencing — this is very similar to the sensitivity we would expect from whole genome sequencing. Other reports (Xu et al., Lauw et al.) use much more sensitive allele-specific PCR testing to detect very low levels of the variant (0.25% and 0.1% respectively); levels this low would typically be rejected as sequencing errors when analyzing genotyping or sequencing data.

Nielsen et al. report significantly increased rates of myeloproliferative and other hematologic cancers were later reported for the individuals found to carry the variant: of 15 individuals without diagnosis of hematologic cancer at the time of blood sample, 4 developed some sort of hematologic cancer in the 18 years that followed, 2 of which were myeloproliferative disorders. (Note that these are all retrospective analyses of records; patients were not specifically monitored for this disease, and so others may have gone undiagnosed.) According to Figure 1, individuals still living after 5-10 years had around a 50% chance of some type hematologic cancer (note that these are extremely small numbers, however, and so a lot of uncertainty exists). Also note that polycythemia vera, essential thrombocytosis, and primary myelofibrosis are described “myeloproliferative cancer” in this study — these myeloproliferative diseases cause excess amounts of blood cells but are not typically called “cancer”.

This variant was found in a large number of cases of myeloproliferative disorders: 71 of 73 patients with polycythaemia vera (97%), 29 of 51 with essential thombocythaemia (57%), and 8 of 16 with idiopathic myelofibrosis (50%). The mutation was detected in granulocytes, which are descended from a myeloid precursor. In 30 cases T-cells (instead descending from a lymphoid precursor) were tested and found not to carry the mutation, indicating this variant is always, or almost always, an acquired mutation and not inherited.

The mutation was not detected in 90 control samples (from a population with type I diabetes).

Functional data in this study confirms the effect of this variant as having an activating effect on JAK2. The authors found that the JAK2-V617F protein was constitutively active in the absence of erythropoietin & erythropoietin receptor signalling while wild type was not, and even more active (and more active than the wildtype control) when Epo and EpoR were both present.

Because many patients also have a loss of heterozygosity in the JAK2 gene leading to homozygosity for JAK2-V617F, the authors also tested whether the wildtype JAK2 has an effect on JAK2-V617F’s activation. They found cotransfection with wild type JAK2 abolished JAK2-V617F’s increased activity.

Expressing the JAK2-V617F mutant in cells lines dependent on growth factors created cell lines that could grow independent of growth factors, while control cells (with wildtype JAK2 or no treatment) died within 36 hours. With JAK2-V617F, the new cell line could be maintained for several weeks without growth factors and had a growth rate comparable to control cells on growth factors.

To test the in vivo effect of JAK2-V617F, mice were transplanted with bone marrow cells containing either JAK2-V617F, wild type JAK2 (control), or an empty vector (control). The mice receiving the JAK2-V617F bone marrow had significantly increased portion of their blood consisting of red blood cells (60% by volume), while untreated and control mice had levels around 40-42%.

A variety of patients with myeloproliferative disorders were profiled, sorted by self-reported disease status. Out of 164 genotyped individual with polycythaemia vera 84% carried the variant — 26 did not have the mutation, 80 were heterozygous, and 41 homozygous (presumably due to loss of heterozygosity). Of 115 genotyped with essential thrombocythemia 32% carried the variant — 78 did not have the mutation, 34 were heterozygous, and 3 were homozygous. Of 46 with myeloid metaplasia with myelofibrosis 35% carried the variant — 30 did not have the mutation, 12 were heterozygous, and 4 were homozygous.

In addition, the study genotyped this position in 269 samples from a panel collected by the International HapMap Consortium, all were homozygous for the wild-type variant. However, many of these were trios, only 420 of the 540 chromosomes tested were independent (120 from Utah NW European, 120 from Nigeria Yoruban, 90 from Han Chinese, 90 from Japanese) — assuming the one failed test accounts for a single individual, this represents 418 unrelated chromosomes found to carry the wild-type variant (equivalent to 209 individuals).

Of 128 patients with polycythemia vera 65% carried the variant — 48 were heterozygous for the variant, and 35 were homozygous for it. Of 93 patients with essential thrombopenia 23% carried the variant — 18 were heterozygous for it, 3 homozygous. Of 23 patients with idiopathic myelofibrosis 57% carried the variant — 8 were heterozygous for it, 3 homozygous.

Of 71 healthy controls, none had this variant. This was also true for 9 patients with chronic myelogenous leukemia and 11 with secondary erythrocytosis.

This study also studies the incidence of the JAK2 V617F variant in patients with myeloproliferative disorders. Of 160 healthy controls tested, none carried the variant. The variant was also not seen in 28 cases of systemic mastocytosis, 35 cases of chronic or acute myeloid leukemia, and 4 cases of secondary erythrocytosis.

Of 72 polycythemia vera patients, 58 (81%) had this variant and 24 of these were homozygous. Of 59 essential thrombopenia patients, 24 (41%) had the variant and 4 of these were homozygous. Of 35 idiopathic myelofibrosis patients, 15 (43%) had this variant and 10 were homozygous.

The authors also explored presence of this variant in rarer myeloproliferative disorder subtypes. Of 134 patients with idiopathic hypereosinophilic syndrome, 2 (1.5%) had the variant, both were homozygous. In addition, they examined related diseases which have some overlap: atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) (both combined in a group as “CML-like MPDs”) and atypical, unclassified cases of myeloproliferative disorder (unclassified MPD). Of 99 cases of CML-like MPDs, 17 (17%) carried the variant, 8 of which were homozygous. Of 53 cases of unclassified MPD, 13 (25%) carried the variant, 7 of which were homozygous.

Using an allele-specific PCR method as a highly sensitive assay for presence of this variant (as low as 0.25% — similar to what was done by Lauw et al.), these authors report 37 samples from a total of 3935 (~1%) test positive for the mutation. Only one of these had blood test results consistent with polycythemia vera. On average the samples did have higher white blood cell and platelet counts; the authors conclude that the mutation may be a prelude to myeloproliferative disease but does not by itself diagnose it.

Of 10,507 participants in the Copenhagen City Heart Study, 18 were found to have this variant. (The authors describe using the assay technique described by Baxter et al., which implies only an examination of sequencing traces — much less sensitive than some other detection techniques used e.g. by Lauw et al.) For overall survival of these individuals in the 17.6 years of follow-up, all 18 of these mutation carriers died. For comparison, an age-matched subset of 540 had only 348 die during this interval (64%) — this different was highly significance (p=0.00003).

Of these 18, 11 had no cancer at the time of blood sampling. 7 of these (63%) later developed some sort of cancer in the subsequent time period, compared to 129 out of 473 in the age-matched population (27%) — p=0.0001 for a difference.

Of the 18, 15 were known to have no myeloproliferative or other hemotologic cancer at the time of blood sampling. Two of these went on to develop myeloproliferative cancer (p=7*10^-22) and, in total, four went on to develop some type of hemotologic cancer (including the two with MPD), a significance of p=2*10^-32.

The authors conclude, “These results document that, in some cases, presence of the mutation precedes the clinical diagnosis of myeloproliferative cancer.” The authors also note that it is possible others of the 18 individuals had myeloproliferative disorders that had been undiagnosed or misdiagnosed, as they were not being studied with the specific intent of collecting data regarding myeloproliferative cancer.

Because venous thromboembolism can be the first symptom presenting when detecting myeloproliferative disorders (myeloproliferative neoplasms = MPN in this paper), these authors were curious if there was a higher rate of the JAK2 V617F variant (associated with MPN development) and MPN symptoms in patients with deep vein thrombosis. They screened 178 patients and 198 controls (without history of venuous thromboembolism) and found four patients and one control positive for this variant (individuals tested as positive if they had 0.1% of the V617E allele in DNA from whole blood).

None of these five had features of MPN, nor did they have these features upon later reassessment (47-85 months, median 68.5 months = 5 years 8.5 months). On reassessment the mutation was still detected in 3 of the 5.